ABSTRACT The central goal of this proposal is to explore pathological hallmarks of Alzheimer?s disease (AD) and associated inflammation in retinas from post-mortem humans and in live mouse models. These studies will provide the basic pathological information to permit development of second-generation retinal imaging methods to diagnose, assess progression, and monitor treatments for AD. The hallmark pathological signs of AD in the brain ? amyloid ?-protein (A?) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau protein ? are also present in the retina. The retina exhibits a wide spectrum of pathologies in AD patients, including thinning of the nerve fiber layer, vascular changes, and degeneration of retinal ganglion cells. However, only recently were AD-specific hallmark A? deposits identified by our group in retinas of AD patients and early-stage cases. Further, our preliminary data indicate manifestation of vascular amyloid deposits and retinal inflammation (e.g. astrogliosis, microgliosis) surrounding A? aggregation and NFT-like structures, which are specific to the retinas of AD patients. To visualize amyloid pathology, we developed a noninvasive retinal curcumin imaging approach for repeated monitoring of retinal A? deposits with high resolution and specificity in living transgenic mouse models of AD. Preliminary studies also demonstrate the feasibility of using an optical imaging device to track infiltration of fluorescently labeled immune cells into the live mouse retina. Data from ongoing clinical trials implementing this retinal curcumin imaging technology demonstrate its capacity to quantitatively detect retinal A? deposits in living AD patients, but establishing specificity for AD and the ability to faithfully predict cerebral pathology during disease progression presents a significant challenge. In this study, paired samples of retina and brain from subjects with AD with or without cerebral amyloid angiopathy and from controls including mild cognitive impairment will be assessed for the spatial distribution of AD-related and inflammatory markers; retinal findings will be correlated with those in the corresponding brain. The following research objectives are proposed: 1) to determine the existence and distribution of abluminal and vascular A? deposits, intracellular A? oligomers, and tauopathy during disease progression in the retina of AD and MCI patients, and to compare retinal pathology to that in the paired brain sample; 2) to investigate the A?-associated local inflammation, infiltrating monocytes and their involvement in A? uptake, and co-occurrence of astrogliosis and glial cell death in retinas of AD and MCI patients; and 3) to noninvasively monitor formation and clearance of retinal A? deposits and monocytes infiltration during disease progression and in response to immune-based therapy in live mouse models of AD. Results from these studies stand to markedly increase the understanding of how AD affects the retina. Given its accessibility for direct, noninvasive high-resolution imaging, targeting this CNS tissue may provide a key axis to investigate and identify new biomarkers that facilitate prediction of risk, diagnosis, and monitoring of AD.